Herbal extract of Wedelia chinensis attenuates androgen receptor activity and orthotopic growth of prostate cancer in nude mice.

PURPOSE: Wedelia chinensis is a common ingredient of anti-inflammatory herbal medicines in Taiwan and southern China. Inflammation is involved in promoting tumor growth, invasion, and metastasis. This study aims to test the biological effects in vivo of W. chinensis extract on prostate cancer. EXPERIMENTAL DESIGN: The in vivo efficacy and mechanisms of action of oral administration of a standardized extract of W. chinensis were analyzed in animals bearing a subcutaneous or orthotopic prostate cancer xenograft. RESULTS: Exposure of prostate cancer cells to W. chinensis extract induced apoptosis selectively in androgen receptor (AR)-positive prostate cancer cells and shifted the proportion in each phase of cell cycle toward G(2)-M phase in AR-negative prostate cancer cells. Oral herbal extract (4 or 40 mg/kg/d for 24-28 days) attenuated the growth of prostate tumors in nude mice implanted at both subcutaneous (31% and 44%, respectively) and orthotopic (49% and 49%, respectively) sites. The tumor suppression effects were associated with increased apoptosis and lower proliferation in tumor cells as well as reduced tumor angiogenesis. The antitumor effect of W. chinensis extract was correlated with accumulation of the principle active compounds wedelolactone, luteolin, and apigenin in vivo. CONCLUSION: Anticancer action of W. chinensis extract was due to three active compounds that inhibit the AR signaling pathway. Oral administration of W. chinensis extract impeded prostate cancer tumorigenesis. Future studies of W. chinensis for chemoprevention or complementary medicine against prostate cancer in humans are thus warranted.

A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through antiproliferation and proapoptosis.

Androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers (PCa). As recurrent tumors restore AR activity independent of hormones, new therapies that abolish AR activity have been sought to prevent or delay the emergence of ablation-resistant disease. Here, we report that a novel abietane diterpene, 6-hydroxy-5,6-dehydrosugiol (HDHS), isolated from the stem bark of Cryptomeria japonica, was a potent AR antagonist in PCa cells. HDHS treatment of androgen-dependent LNCaP and androgen-responsive 22Rv1 cells induced apoptosis as shown by nucleosome release, activation of caspase-3 and caspase-7, and cleavage of poly(ADP-ribose) polymerase accompanied with concomitant up-regulation of tumor suppressor p53. HDHS also decreased the protein expression of cyclins (D1 and E), cyclin-dependent kinases (CDK2, CDK4, and CDK6), and retinoblastoma phosphorylation in PCa cells, which suggest cell cycle arrest in the G(1) phase. Oral administration of HDHS at 0.5 and 2.5 mg/kg once daily for 24 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 22% and 39%, respectively, in association with decreased proliferation and increased apoptosis in tumor cells, which further correlated with increased levels of HDHS in plasma and tumors. Overall, our data suggest that HDHS has potential for use in chemoprevention and chemotherapy of PCa.

Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells.

Chronic inflammation can augment tumor development in various types of cancers, including prostate cancer (PCa). Reduction of inflammation is therefore an important anticancer therapeutic opportunity. Here, we report four anti-proliferative phytocompounds in Wedelia chinensis, an oriental herbal medicine, identified through their ability to modulate the androgen receptor (AR) activation of transcription from prostate-specific antigen promoter in PCa cells. The 50% inhibition concentration values of indole-3-carboxylaldehyde, wedelolactone, luteolin and apigenin, were 34.9, 0.2, 2.4 and 9.8 muM, respectively. A formula that combined the phytocompounds in the same proportions as in the herbal extract decreased the dosage of each compound required to achieve maximal AR inhibition. In correlation with the AR suppression effect, these active compounds specifically inhibited the growth of AR-dependent PCa cells and as a combination formula they also synergistically suppressed growth in AR-dependent PCa cells. Our study has identified synergistic effects of active compounds in W. chinensis and demonstrated their potential in PCa prevention and therapy. The paradigm of multiple activities and synergism is a useful framework to investigate the therapeutic effects of whole extracts from assorted medicinal plant species.

Diterpenes from Cryptomeria japonica inhibit androgen receptor transcriptional activity in prostate cancer cells.

We identified eight diterpenes from Cryptomeria japonica (Taxodiaceae), which inhibit the activity of the androgen receptor (AR) in human prostate cancer (PCa) 22Rv1-derived 103E cells. The compounds 6,12-dihydroxyabieta-5,8,11,13-tetraen-7-one ( 2), sugiol ( 3), ferruginol ( 4), and 5-epixanthoperol ( 7) have near 100 % AR inhibition efficacy at concentrations of 10, 5, 25, and 25 microM, respectively. Because these compounds have very similar structures, analysis of their differential activity may aid in the design of inhibitors for PCa treatment.

An ionizable chromophoric reagent for the analysis of primary amine-containing drugs by capillary electrophoresis.

We found that ofloxacin acyl chloride is a potential chromophoric reagent for labeling amino analytes for capillary electrophoresis. Ofloxacin acyl chloride has a tertiary amino function in its structure and the derivatives from ofloxacin acyl chloride reacting with amino analytes can be ionized by an acid treatment and analyzed by simple capillary zone electrophoresis. Ofloxacin acyl chloride was used to derivatize model analytes (without chromophore) of amantadine (amino drug), tranexamic acid (non-protein amino carboxylic acid), glycine, and methionine (protein amino acids). The resulting derivatives were analyzed by capillary zone electrophoresis with ultraviolet detection (300 nm). The detection limits of the analytes studied were in the range of 1.0-2.5 microM (S/N = 3, injection 3 s). The precision (relative standard deviation) and accuracy (relative error) of the method for intra- and inter-day analyses of the analytes were respectively below 4.5% and 3.9%. Application of the method to the analysis of tranexamic acid in plasma proved feasible.

Highly sensitive analysis of iodide anion in seaweed as pentafluorophenoxyethyl derivative by capillary gas chromatography.

A simple and sensitive gas chromatography (GC) method is described for the trace analysis of iodide anion (iodide) in processed seaweed as an organic derivative. The method is based on the derivatization of aqueous iodide extracted from seaweed with 2-(pentafluorophenoxy)ethyl 2-(piperidino)ethanesulfonate in toluene using tetra-n-hexylammonium bromide as a phase-transfer catalyst. The resulting pentafluorophenoxyethyl iodide is highly responsive to an electron-capture detector (ECD) and was analyzed by GC-ECD, giving a low detection limit of approximately 2.7 nM (2.7 fmol/microL injected). Interferences of some common anions in the analysis of iodide were studied and proved to be minimal. Application of the method to the analysis of iodide in processed seaweed was performed.